Preparation of n-substituted isothiazolinone derivatives

ABSTRACT

Provided is a process for the preparation of an N-substituted isothiazolinone derivative having the general formula (I), comprising reacting N-substituted 3-mercaptopropionamides of formula (II) or N,N′-bis-substituted 3,3′-dithiodipropionamides of formula (III) with sulfuryl chloride in the absence of solvents. Also provided is a process for the preparation of a compound having the general formula (III), comprising reacting a methyl ester of formula (IV) with an amine of formula (V) in a solvent of methanol. As no addition solvent is used in the process of the invention, the cost of manufacturing and pollution to the environment can be reduced.

FIELD OF THE INVENTION

The present invention relates to the preparation of isothiazolinonederivatives, and more specifically, to the preparation of N-substitutedisothiazolinone derivatives.

BACKGROUND OF THE INVENTION

Isothiazolinone compounds are a novel kind of potent and broad-spectrumantiseptics possessing the advantages of high potency, low toxicity, along effective period and harmlessness to the environment overconventional antiseptics. Therefore, isothiazolinone compounds havebroad applications in the fields of water treatment, cosmetics,construction materials, binding agents, paints, medical treatment,fabrics, photographs and detergents, and especially can be used asantifouling agents in marine antifouling coatings.

Till now, a number of methods for preparing N-substitutedisothiazolinone derivatives have been reported, most of which comprisethe step of reacting a N,N′-bis-substituted dithiodipropionamide or aN-substituted mercaptopropionamide with a halogenating agent in anorganic solvent.

For example, Chinese Patent Applications CN1634889 and CN1629148disclose, respectively, processes for preparing N-alkoxypropylisothiazolinones and N-alkoxyethoxyl propylisothiazolinones, whichcomprise reacting the corresponding N,N′-bis-substituteddithiodipropionamides with sulfuryl chloride in ethyl acetate.

Japanese Patent Application JP2003-335763 discloses a process for thepreparation of 2-substituted-4-isothiazolin-3-ones, which comprisesreacting N-substituted mercaptopropionamides or N,N′-bis-substituteddithiodipropionamides with a halogenating agent in ethyl acetate.

European Patent Application EPO498347 discloses a process for thepreparation of 2-methyl-isothiazolin-3-ones, which comprises reactingN-methyl-3-mecaptopropionamides with chlorine in a solvent of aromaticor halogenated hydrocarbon, such as benzene, toluene, chlorobenzene,chloroform and the like.

European Patent Application EP1113012 discloses a process for thepreparation of 2-alkyl-4-isothiazolin-3-ones, which comprises reactingN-alkyl mecaptopropionamides or N,N′-dialkyl dithiodipropionamides witha chlorinating agent in a solvent, in which hydrogen chloride isinsoluble or has low solubility, such as halogenated aliphatichydrocarbons, halogenated aromatic hydrocarbons or aliphatichydrocarbons.

U.S. Pat. No. 5,453,507 discloses a process for the preparation ofN,N′-dimethyl or N,N′-di-n-octyl-4-isothiazolin-3-ones, which comprisesreacting N,N′-bis-substituted dithiodipropionamides with sulfurylchloride in a halogenated organic solvent, such as CH₂X₂, CHX₃, CX₃CH₃and CHX₂CHX₂.

However, the use of organic solvents in the processes of the prior artcauses a lot of problems. For example, firstly the use of the solventwill decrease the volumetric efficiency of the reactor therebydecreasing the productivity; secondly the post-treatment and recovery ofthe solvent will increase the operation cost; thirdly the solvent willbring impurities into the reaction system thereby complicating theseparation and purification of the desired products; and lastly theorganic solvent used, especially benzene and halogenated hydrocarbons,generally has an adverse effect on the environment.

SUMMARY OF THE INVENTION

The present invention aims at providing an improved process for thepreparation of N-substituted isothiazolinone derivatives, which is morecost-effective and less harmful to the environment.

According to an aspect of the invention, there is provided a process forthe preparation of a compound having the following general formula (I),

in which

R¹ is selected from the group consisting of alkyl, cycloalkyl and aryl,optionally substituted by a substituent selected from the groupconsisting of alkyl, aryl, alkoxy and aryloxy; and

R² and R³, each independently, represent hydrogen or chlorine,comprising:

reacting a compound having the following general formula (II),

in which R¹ is as previously defined, or a compound having the followinggeneral formula (III),

in which R¹ is as previously defined,

with sulfuryl chloride in the absence of a solvent.

According a preferred embodiment of the invention, R¹ is selected fromthe group consisting of C₁-C₈ alkyl, C₃-C₈ cycloalkyl and C₆-C₁₀ aryl,optionally substituted by a substituent selected from the groupconsisting of C₁-C₈ alkyl, C₆-C₁₀ aryl, C₁-C₈ alkoxy and C₆-C₁₀ aryloxy.More preferably, R′ represents C₁-C₈ alkyl optionally substituted byC₆-C₁₀ aryl or C₁-C₈ alkoxy.

According to another preferred embodiment of the invention, R² and R³both represent hydrogen or chlorine.

Preferably, the reaction is carried out at a temperature between about−10° C. and about 75° C., and more preferably between room temperatureand about 45° C.

According to the process of the invention, N-substituted isothiazolinonederivatives can be prepared in the absence of a solvent, and thereforeproblems caused by using an organic solvent in the prior art can beavoided, and the cost of manufacturing and pollution to the environmentcan be greatly reduced.

According to another aspect of the invention, there is provided aprocess for the preparation of a compound having the following generalformula (III), comprising the step of reacting a compound having formula(IV),

with a compound having the general formula (V),

H₂N—R¹   (V)

in which R¹ is as previously defined,

in a solvent of methanol.

According to a preferred embodiment of this process in the invention,the molar ratio of the compound of formula (IV) to the compound offormula (V) is between about 1:2.0 and 1:2.6. The temperature of thereaction is preferably between about −15° C. and about 65° C.

According to the process of the invention, no further impurities will begenerated into the reaction system during the preparation of thecompound of formula (III), and the separation and purification thereofcan be greatly simplified in comparison with processes in the prior art.

DETAILED DESCRIPTION OF THE INVENTION

As described above, in an aspect of the invention, there is provided aprocess for the preparation of an N-substituted isothiazolinonederivative having the following general formula (I),

in which

R¹ is selected from the group consisting of alkyl, cycloalkyl and aryl,optionally substituted by a substituent selected from the groupconsisting of alkyl, aryl, alkoxy and aryloxy; and

R² and R³, each independently, represent hydrogen or chlorine,comprising the step of reacting an N-substituted 3-mercaptopropionamidehaving the following general formula (II),

in which R¹ is as previously defined, or

an N,N′-bis-substituted 3,3′-dithiodipropionamide having the followinggeneral formula (III),

in which R¹ is as previously defined,

with sulfuryl chloride in the absence of a solvent.

The term “alkyl”, as used herein, generally refers to a straight orbranched saturated aliphatic hydrocarbon group, preferably C₁-C₁₀ alkyl,and more preferably C₁-C₈ alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl and the like.

The term “cycloalkyl”, as used herein, generally refers to a saturatedalicyclic hydrocarbon group, preferably C₃-C₁₀ cycloalkyl, and morepreferably C₃-C₈ cycloalkyl, such as cyclopropyl, cyclobutyl,cyclopentyl and the like.

The term “aryl”, as used herein, generally refers to an aromatichydrocarbon group, preferably C₆-C₂₀ aryl, more preferably C₆-C₁₀ aryl,such as phenyl and naphthyl, and most preferably phenyl.

The term “in absence of a solvent”, as used herein, means that, exceptthe reactants themselves, no other substances are added to the reactionsystem to dissolve the reactants, intermediates or products.

During the preparation of isothiazolinone derivatives according to theprocess of the invention, sulfuryl chloride in the reaction system actsas both the reactant and the solvent at the beginning of the reaction;and after sulfuryl chloride is depleted, the resultant isothiazolinonederivative acts as a solvent, and therefore no addition solvent isneeded.

In particular embodiments of the invention, the desired product can beseparated using well-known techniques including, but not limited to,recrystallization and solvent extraction.

In a preferred embodiment of the invention, R¹ represents C₁-C₈ alkyloptionally substituted by C₆-C₁₀ aryl or C₁-C₈ alkoxy. More preferably,R¹ represents C₁-C₈ alkyl, especially n-octyl.

In another preferred embodiment of the invention, R² and R³ bothrepresent hydrogen or chlorine.

In some preferred embodiments, the process of the invention comprisesreacting a compound of formula (II) with sulfuryl chloride. Morepreferably, the molar ratio of the compound of formula (II) to sulfurylchloride is between about 1:1 and 1:11.

In other embodiments of the invention, chlorine can be used in additionto surfuryl chloride as a chlorinating agent.

In a preferred embodiment, the process of the invention comprisesreacting a compound of formula (III) with sulfuryl chloride optionallyin the presence of chlorine. More preferably, the molar ratio betweenthe compound of formula (III), sulfuryl chloride and chlorine is about1:1-11:0-11, and further more preferably about 1:1-3:5-7.

In a particularly preferred embodiment, the process of the inventionfurther comprises the step of preparing a compound of formula (III),which comprises reacting dimethyl 3,3′ -dithiodipropionate of formula(IV),

with an amine having the general formula (V),

H₂N—R¹   (V)

in which R¹ is as previously defined,

in a solvent of methanol.

More preferably, the molar ratio of the compound of formula (IV) to thecompound of formula (V) is between about 1:2.0 and 1:2.6. Thetemperature of the reaction between the compound of formula (IV) and thecompound of formula (V) is preferably between about −15° C. and about65° C., and more preferably between about 5° C. and room temperature.The reaction time is about 3 hours to 5 days.

In another aspect of the invention, there is provided a process for thepreparation of a compound of formula (III), comprising reacting dimethyl3,3′-dithiodipropionate of formula (IV),

with an amine having the general formula (V),

H₂N—R¹   (V)

in which R¹ is as previously defined,

in a solvent of methanol.

Preferably, R¹ represents C₁-C₈ alkyl optionally substituted by C₆-C₁₀aryl or C₁-C₈ alkoxy. More preferably, R¹ represents C₁-C₈ alkyl,especially n-octyl.

And preferably, the molar ratio of the compound of formula (IV) to thecompound of formula (V) is between about 1:2.0 and 1:2.6. The reactiontemperature is preferably between about −15° C. and about 65° C., andmore preferably between about 5° C. and room temperature. The reactiontime is about 3 hours to 5 days.

As methanol is a product of the reaction between the compound of formula(IV) and the compound of formula (V), use of methanol as a solvent inthe process of the invention would not introduce into the reactionsystem any undesired impurity. Thus, the separation and purification ofthe desired product can be greatly simplified. More specifically, incomparison with processes where water is used as a solvent, the productobtained according to the process of the invention has a greaterparticle size and therefore can be easily separated from the motherliquor. And according to the process of the invention, the remainingmother liquor can be recycled and methanol can be recovered byevaporation. As a result, waste emission to the environment is greatlyreduced.

EXAMPLES

Hereinafter, preferred embodiments of the invention will be illustratedin detail with reference to the following examples, which should beconsidered only illustrative and non-limitative.

Example 1 Preparation of N,N′-di-n-octyl-3,3′-dithiodipropionamide

The reaction scheme is as follows:

(SCH₂CH₂CO₂CH₃)₂+2C₈H₁₇NH₂→(SCH₂CH₂CONHC₈H₁₇)₂+2CH₃OH

238 g (1 mol) of dimethyl 3,3′-dithiodipropionamide and 280 g (2.17 mol)of n-octylamine were added into 300 ml of methanol in a 1,000 mlreaction flask, and the reactants stirred at 5° C. for 5 days (undernitrogen atmosphere, if desired). The reaction mixture was then cooledto −10° C., and separated by centrifuging to give 329 g of a solid ofN,N′-di-n-octyl-3,3′-dithiodipropionamide (purity >95%, yield 76%). Themother liquor was recycled after methanol was recovered by evaporation.

Example 2 Preparation of N-n-octyl isothiazolinones (includingN-n-octyl-4-isothiazolin-3-one (OIT) andN-n-octyl-4,5-dichloro-4-isothiazolin-3-one (DCOIT))

The reaction scheme is as follows:

200 ml (330 g, 2.44 mol) of sulfuryl chloride was added into a 1,000 mlreaction flask, to which 648 g (1.5 mol) ofN,N′-di-n-octyl-3,3′-dithiodipropionamide was then added for 6.5 hours(about 100 g per hour) under agitation. After 3 hours of reaction,chlorine was aerated into the reaction mixture at about 50 g per hourfor 13 hours (about 650 g in total, 9.15 mol). When the temperature ofthe reaction mixture reached 40° C., the mixture was cooled with salineand maintained at a temperature of 40-45° C. After the aeration ofchlorine was completed, the reaction mixture was stirred at the sametemperature for 2 hours.

The reaction mixture was washed with hot water at 50° C. in another1,000 ml reaction flask till it became weakly acidic, and, if desired,sodium bicarbonate was used to neutralize excessive acid. Theprecipitate was recrystallized in methanol to give 190 g of DCOIT(purity >95%). The recrystallization mother liquor was then extractedsuccessively with petroleum ether and methanol to afford 61g of OIT(purity >93%, yield 19%) and 49 g of DCOIT (purity >95%). The totalyield of DCOIT is 56.5%.

It should be understood that although the present invention has beenspecifically disclosed by the preferred embodiments and examples,modifications and variations thereto, without departing from the spiritof the invention, may be pursued by those skilled in the art, and suchmodifications and variations should fall within the scope of theinvention.

1-10. (canceled)
 11. A process for the preparation of a compound havingthe general formula (III),

wherein R¹ is selected from the group consisting of C₁-C₈ alkyl, C₃-C₈cycloalkyl and C₆-C₁₀ aryl, optionally substituted by a substituentselected from the group consisting of C₁-C₈ alkyl, C₆-C₁₀ aryl, C₁-C₈alkoxy and C₆-C₁₀ aryloxy, comprising reacting, in a solvent ofmethanol, a compound of formula (IV),

with a compound having formula (V),H₂N—R¹   (V) wherein R¹ is as previously defined.
 12. The processaccording to claim 11, wherein the molar ratio of the compound offormula (IV) to the compound of formula (V) is between about 1:2.0 and1:2.6.
 13. The process according to claim 11 or 12, wherein the reactionbetween the compound of formula (IV) and the compound of formula (V) iscarried out at a temperature between about −15° C. and about 65° C. 14.The process according to claim 11, wherein R¹ is C₁-C₈ alkyl.
 15. Theprocess according to claim 11, wherein R¹ is n-octyl.
 16. The processaccording to claim 11, wherein the reaction between the compound offormula (IV) and the compound of formula (V) is carried out at atemperature between about 5° C. and room temperature.
 17. The processaccording to claim 11, wherein the reaction between the compound offormula (IV) and the compound of formula (V) is carried out for about 3hours to 5 days.